Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities due to cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF).
Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E. L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(1):264-7 Jan. 1992). Its prevalence is likely to increase as the population ages and it is estimated that 3-5% of patients over the age of 60 years have AF (Kannel W. B., Abbot R. D., Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018-22, 1982; Wolf P. A., Abbot R. D., Kannel W. B. Stroke. 22(8):983-8, 1991). While AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton R. C., Kistler J. P., Fallon J. T., Friedlich A. L., Fisher C. M., American Journal of Cardiology 40(4):509-13, 1977; Wolf P. A., Abbot R. D., Kannel W. B., Archives of Internal Medicine 147(9):1561-4, 1987; Wolf P. A., Abbot R D., Kannel W. B. Stroke. 22(8):983-8, 1991; Cabin R. S., Clubb K. S., Rall C., Perlmutter R A., Feinstein A. R, American Journal of Cardiology 65(16): 1112-6, 1990).
Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia.
WO95/08544 discloses a class of aminocyclohexylester compounds as useful for the treatment of arrhythmias.
WO93/19056 discloses a class of aminocyclohexylamides as useful in the treatment of arrhythmia and in the inducement of local anaesthesia.
WO99/50225 and WO 04/099137 disclose aminocyclohexylether compounds as being useful for the treatment of arrhythmias.
WO06/138673 and WO 06/88525 describe processes for preparing aminocyclohexylether compounds
This invention relates to a process for preparing aminocyclohexyl ether compounds via functionalization of a cyclohexyl amine. The invention is also related to a process that utilizes etherification of a racemic intermediate, as well as a dynamic kinetic resolution-transamination step. The instant invention is less expensive than previous processes since provides a stereoselective product using inexpensive starting materials.